Cytotoxic & MDR-Active Alkaloids-Synthesis & Evaluation

细胞毒性

• 批准号: 6561727
• 负责人: Joseph Paul Konopelski
• 金额: $ 29.05万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561727
• 关键词: P glycoprotein; SCID mouse; alkaloids; carbopolycyclic compound; cytotoxicity; drug design /synthesis /production; isothiocyanates; laboratory mouse; multidrug resistance

DESCRIPTION (provided by applicant): The principle objectives of this research project are the synthesis, in enantiomerically pure form, of diazonamide A (revised structure, 1) and N-methylwelwitindolinone C isothiocyanate (2). The specific aims will focus on six challenges: 1. The first aim is an efficient synthesis of the desired stereochemistry at the C10/C11 centers as an advanced fragment leading to diazonamide A. Aryllead(IV) compounds are highly selective and mild reagents for the production of quaternary centers. Our studies in this area have been especially fruitful. 2. The second aim is the execution of an effective aryl-aryl coupling reaction to set the C16/C18 bond. Organometallic technology can be employed to perform this aryl-aryl coupling reaction. Many such examples exist in the literature, and our own studies concur with this assessment. 3. The third aim is the efficient synthesis of the bis-oxazole system in conjunction with generation of the macrobicyclic structure of diazonamide A. Cyclodehydration of a N-acyI-D-aminoketone will effectively generate the C29 through C31 oxazole, whereas the C26 through C28 chlorooxazole can be effectively prepared via a [3+2] cycloaddition strategy. 4. The fourth aim is the efficient synthesis of the entire ring system of N-methylwelwitindolinone C isothiocyanate. An intramolecular conjugate addition reaction between C3 and C16, coupled with an efficient intermolecular coupling of the indole C4 position with C11, will efficiently generate the central sevenmembered ring of 2. 5. The fifth aim is the successful synthesis of the C11/C12 array of stereocenters in Nmethylwelwitindolinone C isothiocyanate. Directed introduction of functionality at C12 from C11 will allow both centers to be developed simultaneously. 6. The sixth specific aim is the synthesis of selected derivatives of both these targets for biological testing and evaluation. Collaborations for testing have been established. Diazonamide A is a cytotoxic agent and Nmethylwelwitindolinone C isothiocyanate is a multidrug resistance (MDR) reversal agent. Only a vigorous synthetic program toward these natural products and selected derivatives will allow for their full examination both as biological agents for cell cycle study and as possible therapeutics.

描述（由申请人提供）：本研究项目的主要目的是以对构象纯形式合成重氮酰胺A（修订结构，1）和n -甲基威氏吲哚啉酮C异硫氰酸酯(2)。具体目标将集中在六个挑战上：1。第一个目标是在C10/C11中心高效合成所需的立体化学，作为导致重氮酰胺a的高级片段。芳基铅（IV）化合物是生产季中心的高选择性和温和的试剂。我们在这方面的研究特别有成果。2. 第二个目标是执行一个有效的芳基-芳基偶联反应来设置C16/C18键。有机金属技术可用于芳基-芳基偶联反应。文献中有许多这样的例子，我们自己的研究也与这一评估相一致。3. 第三个目标是高效合成双恶唑体系并生成重氮酰胺a的大双环结构。n -酰基- d -氨基酮的环脱水可有效生成C29 - C31恶唑，而通过[3+2]环加成策略可有效制备C26 - C28氯恶唑。4. 第四个目标是高效合成n -甲基威维吲哚酮C异硫氰酸酯的全环体系。C3和C16之间的分子内共轭加成反应，加上吲哚C4位置与C11的有效分子间偶联，将有效地生成2的中心七元环。5. 第五个目标是成功合成Nmethylwelwitindolinone C异硫氰酸酯的C11/C12立体中心阵列。有针对性地将C11的功能引入C12，将允许两个中心同时开发。6. 第六个具体目标是合成这两种目标的选定衍生物，用于生物学测试和评价。已经建立了测试方面的合作。重氮酰胺A是一种细胞毒性药物，异硫氰酸Nmethylwelwitindolinone C是一种多药耐药（MDR）逆转剂。只有对这些天然产物和选定的衍生物进行有力的合成程序，才能使它们作为细胞周期研究的生物制剂和可能的治疗药物得到充分的检验。